PROJECT SUMMARY Metabolic syndrome (MetSyn) is a group of metabolic conditions that occur together and promote the development of cardiovascular disease (CVD) and type 2 diabetes. Although various criteria for defining MetSyn exist, disease conditions include abdominal obesity, insulin resistance, elevated serum triglyceride levels, depressed serum high-density lipoprotein (HDL) levels, elevated blood glucose levels and hypertension. The incidence of MetSyn is predicted to increase as obesity has become a worldwide epidemic. This increase may have detrimental effects and may actually reverse the trend of decreasing CVD in the US. Heritability estimates for individual components of MetSyn vary between 40% to 70%, suggesting a strong contribution of genetic components to disease pathology. Recent genome-wide association studies (GWAS) have identified over 600 genomic loci that are associated with obesity, diabetes, CVD and cardiometabolic traits. However, most of the underlying genes and the related mechanisms of how these loci contribute to the disease process remain unknown. One of the Type 2 Diabetes GWAS signals at chromosome 7q32.3 has pleiotropic effects as it is also associated with serum HDL levels and body fat distribution. The effects of the genetic variants appear to be stronger in females than in males. This signal maps to a 45kb recombination interval, extending from 3kb upstream of the transcription factor KLF14. Using gene expression data from subcutaneous adipose tissue biopsies collected from participants of the Metabolic Syndrome in Men (METSIM) cohort, we showed that KLF14 is the likely cis-effector gene for this locus and revealed it to be a master trans-regulator of a program of adipose tissue expression. Our results indicated that lower expression of KLF14 was associated with detrimental metabolic profiles in humans. Therefore, we hypothesized that induction of KLF14 abundance and resulting changes in its targets in adipocytes would result in a beneficial metabolic profile. To test this hypothesis, this proposal outlines a multilayered approach to define the trancriptional targets of KLF14 in adipocytes, the impact of the modulation of KLF14 expression on adipocyte function, and explore the therapeutic benefits of adipocyte-specific induction of KLF14 expression in transgenic mice. We will use primary adipocytes, adipocyte cell lines, primary tissues, and transgenic mice to dissect the effects of KLF14 on gene expression and metabolic phenotypes.